Despite remarkable advances in our understanding of the biology of malaria in the last 30 years, malaria elimination, or even control, remains on the distant horizon in most of sub-Saharan Africa. In this proposal, we will define the burden of malaria disease and infection in Malawi and bring to control and elimination efforts the most advanced scientific methods available to apply new interventions, target established ones and assess their impact rapidly and accurately. Malawi is a country hit hard by malaria, it has an excellent collaborative relationship between policy-makers and investigators and the physical and scientific infrastructure to support the novel approaches proposed in this application. The overall goal of Project 1 is to characterize the changing epidemiology of malaria in response to control and elimination efforts in diverse epidemiological settings within Malawi, and to understand how this changing epidemiology affects the burden of malaria disease, the reservoir of malaria infection, and the emergence and spread (or reversal) of resistance to antimalarial drugs. These goals will be accomplished through the following three specific aims: 1) to evaluate the burden of malaria infection and disease in diverse eco-geographic regions of Malawi and in relation to control and elimination interventions, 2) to characterize the parasite population genetics in diverse eco-geographic regions of Malawi and in response to malaria control and elimination interventions and 3) to measure the effect of changes in antimalarial drug policy on the prevalence of drug-resistant parasites. These aims will be accomplished through cross-sectional studies, health facility-based surveillance and small but detailed cohort studies in Blantyre, Thyolo and Chikwawa districts to accurately define the burden of disease and infection and detect sources of transmission. Specimens collected from these sources will undergo genomic analysis for the purposes of assessing the effect of transmission intensity on population genetics, the development of field-appropriate genetic tools for Malawi and for detecting changes in drug-resistance patterns as a result of new drug policies.